Molecular Defect Found That May Cause Heart Failure

Heart Failure Research

A new study has identified a molecular defect in cardiac cells that may be a fundamental cause of heart failure, a progressive weakening of the heart that leaves the organ unable to pump blood through the body.

The findings, by researchers at the Ohio State University Dorothy M. Davis Heart and Lung Research Institute, show that specialized proteins called ryanodine receptors (RyRs) malfunction in the failing heart. The RyRs form channels that become leaky, leading to calcium imbalances that prevent the heart from contracting effectively and relaxing adequately. The condition worsens until the heart can no longer work as a pump.

The root causes of heart failure are not known.

"We found some drastic changes in the way muscle cells in the failing heart handle calcium," says principal investigator Sandor Gyorke, professor of physiology and cell biology at the OSU Davis Heart and Lung Research Institute. "Discovery of this mechanism suggests at least one potential target for treating the causes of this disease in a rational manner."

Currently, the only way to correct heart failure is by heart transplantation.

About 4.9 million Americans are currently living with heart failure, and an estimated 265,000 of them die of it yearly. Those with the condition are at six to nine times greater risk of experiencing sudden cardiac death than someone in the general population. From 1992 to 2002, deaths from heart failure rose 35 percent and the incidence is expected to keep rising.

Calcium plays a fundamental role in muscle contraction, particularly in heart muscle. A heart contraction begins when the heart's pacemaker sends an electrical signal to heart-muscle cells. The electrical signal triggers the release of calcium from a large storage site within each muscle cell. The released calcium activates the muscle cell's contractile machinery, which causes the cell, and the heart as a whole, to contract.

This calcium storage site is known as the sarcoplasmic reticulum (SR), and it resembles a convoluted, flattened sack within the cell. The delicate, membrane-bound walls of the SR are penetrated with thousands of RyR channels. These serve as gate keepers that allow calcium to flood into the cell to initiate contraction.

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The amount of calcium stored in the SR determines the strength of the heart beat and how much blood the heart ejects when it contracts.

At the end of a contraction, the channels close tightly. Molecular pumps, also located in the walls of the SR, then suck the released calcium back into the SR to prepare for the next contraction.

For this study, the OSU investigators used microscopic fluorescence imaging techniques to monitor changes in calcium ion concentrations in the SR and other regions of individual isolated heart cells.

They found that in heart failure, the channels cannot close tightly after a contraction. Instead, they remain partly open throughout the cardiac cycle. This allows some of the calcium to leak out.

This leaves too little calcium in the SR, so strong contrations are not possible, and too much calcium outside SR, so the muscle cells remain slightly contracted and the heart cannot fully relax.

As the condition worsens, the heart grows weaker as a pump.

Gyorke and his colleagues are now working to better understand the damage to the RyR channel.

Funding from the National Heart, Lung and Blood Institute; the American Heart Association; and the OSU Research Foundation supported this research. - COLUMBUS , Ohio

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